The insulin-like growth factor pathway plays a critical role in the growth and development of the uterus. Insulin-like growth factors (IGFs) are potent mitogenic and anti-apoptotic molecules involved in the regulation of cell proliferation and steroid hormone actions in the endometrium. IGF-binding proteins (IGFBPs) modulate the biological actions of IGF by regulating the availability of circulating IGF to target tissues and the binding of IGF to its receptors. Unopposed IGF action may lead to uncontrolled cellular proliferation in the uterus and ultimately lead to the development of endometrial cancer. Local expression of genes encoding IGFs and IGFBPs are important in determining the level of bioactivity in the uterus. Polymorphisms in genes involved in the IGF pathway may alter gene expression and/or protein function, which may ultimately influence endometrial cancer risk. We propose to use the resources of the large, well-characterized cohorts, the Nurses' Health Study (NHS) and the Women's Health Study (WHS), to investigate the association between polymorphisms and haplotypes in candidate genes within the IGF pathway with endometrial cancer risk. Our major hypothesis is that variant allele(s) in key genes involved in the IGF pathway will influence the development of endometrial cancer and interact with reproductive and hormonal risk factors to further alter risk. Our study will be among the few studies able to prospectively examine these issues in two large defined cohorts with complete ascertainment of incident cases and comprehensive prospective information on other endometrial cancer risk factors. We have the largest, to date, population-based case-control study of endometrial cancer with a total of 607 invasive endometrial cancer cases and 1566 matched controls. We will have > 85% power to detect a relative risk 1.50 or greater for the main effects of most of the genotypes and haplotypes of interest. [unreadable] [unreadable] [unreadable]